Malaria and hypertension. Another co-evolutionary adaptation?

Arterial hypertension is a complex multifactorial disease and a global public health concern. It is responsible for at least 45% of deaths due to heart disease and 51% of deaths due to stroke, adding up the tremendous number of 9.4 million deaths every year (Lim et al., 2012; World Health Organization, 2013). The renin-angiotensin-aldosterone system (RAAS) is one of the most important regulatory systems of blood volume, arterial pressure and cardiovascular homeostasis. Angiotensin II (Ang II) is the principal effector hormone of the RAAS in vascular biology, mediating effects via two main receptors: Angiotensin receptor type 1 (AT1) and type 2 (AT2) (Callera et al., 2007). When Ang II binds to AT1 on vascular smooth muscle cells, it mobilizes intracellular Ca2+, leading to cellular contraction. Sustained cellular contraction increases peripheral vascular resistance, resulting in high blood pressure (Touyz and Schiffrin, 2000). Among others, genetic factors are closely related with the development of hypertension. People with African American and South Asian genetic background have higher prevalence of hypertension compared to Caucasians, independently of their socioeconomic status (Cappuccio, 1997; Sampson et al., 2014). These differences in the ethnic background can increase the prevalence of hypertension by 2 fold until the age of 55, when the differences decline, presumably because of the interfering effect of age-related factors (Wolz et al., 2000). Several polymorphisms have been associated with higher prevalence of arterial hypertension; there are 2 polymorphisms in the Angiotensin Converting Enzyme (ACE) and Angiotensin Converting Enzyme 2 (ACE2) that lead to elevate circulating Ang II levels (Giner et al., 2000; Di Pasquale et al., 2004; Fan et al., 2007). Interestingly, these same genetic variations (the “D” allele of ACE I/D polymorphism and the ACE2 C→T substitution) have been associated with a lower incidence of cerebral malaria (CM) in Indian adults, although the later one only in women (Dhangadamajhi et al., 2010). Malaria is still a major public health problem world wide, causing approximately 600,000 deaths, mostly among African children (World Health Organization, 2012a). A high proportion of these deaths are caused by CM, a syndrome characterized by impaired consciousness, generalized convulsions, coma and neurological sequelae (Idro et al., 2005). CM is caused by the interaction between Plasmodium falciparum infected erythrocytes and host brain endothelial cells. Parasite proteins that are expressed on the surface of infected erythrocytes (PfEMP1), interact with host endothelial cell receptors (Protein C receptor, ICAM1; Newbold et al., 1997; Turner et al., 2013) leading to their sequestration within the brain microcirculation. Disruption of the blood-brain barrier is observed producing the characteristic petechiae and ring hemorrhages found on the brain of dead patients with CM (Rasti et al., 2004). Although it is still not well-established that Ang II has beneficial effects onmalaria and particularly on CM, different lines of evidence suggest a possible ‘protective’ effect that could be mediated by different, non-exclusive mechanisms that could affect parasite development and/or host susceptibility to Plasmodium-induced pathology. Recent reports have shown that angiotensin peptides can induce impairment of the erythrocytic cycle of Plasmodium, reducing the parasite growth in vitro (Maciel et al., 2008; Saraiva et al., 2011). Since the development of CM depends on the initial levels of parasitemia in mice (Amani et al., 1998) and possibly in humans (Bejon et al., 2005), this could be a potential explanation for Ang II protection from CM. Our unpublished results using mice infected with Plasmodium berghei seem to confirm that the elevation of Ang II levels results in modestly decreased parasitemias in this animal model. It is possible that Ang II could modulate malaria severity through additional mechanisms, specially, since the inhibitory effect observed in parasite growth is modest (Maciel et al., 2008; Saraiva et al., 2011). Sodium conservation could provide an alternative explanation to the protective effect of the polymorphisms associated with higher levels of Ang II. In this case, Ang II could be acting to counterbalance hyponatremia by stimulating the secretion of aldosterone from the adrenal cortex, the major regulator of Na+ reabsorption. Hyponatremia (serum sodium < 135mmol/L) is frequent in malaria patients and correlates with disease severity in imported malaria (van Wolfswinkel et al., 2010). However, other studies have shown that circulating Na+